2,6-Diazaspiro[3.3]heptanes: Synthesis and Application in Pd-Catalyzed Aryl Amination Reactions

Burkhard, Johannes A.; Carreira, Erick M.

doi:10.1021/ol801293f

Cited by 66 publications

(46 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…28 2,6-Diazaspiro[3.3]heptane 31 was synthesized following chemistry reported by Carreira. 29 Lastly, the aryloxy azetidine core used in the synthesis of analogue 33 followed a synthetic route outlined by Pettersson and co-workers. 30 The synthesis of azepine 28 , azetidine 32 , and a racemic mixture of spiroindane (±)- 34 began with the commercially available secondary amine cores.…”

Section: Chemistrymentioning

confidence: 99%

Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

et al. 2014

View full text Add to dashboard Cite

Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4–/– mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.

show abstract

Section: Chemistrymentioning

confidence: 99%

Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

et al. 2014

View full text Add to dashboard Cite

show abstract

“…In the course of our investigations it was discovered that spirocyclic oxetane 72 was an ideal precursor for the preparation of "homospiropiperazines" (Scheme 13). [57] Selective opening of the oxetane ring with anhydrous HBr gave the bromoalcohol 82, which after conversion into the dibromide was easily cyclized with benzylamine to give the azetidine. This three-step procedure afforded 2,6-diazaspiro [3.3]heptane 83 with differently protected amines in an overall yield of 76 % on a multigram scale.…”

Section: Ring-opening Reactions Of Oxetanesmentioning

confidence: 99%

Oxetanes as Versatile Elements in Drug Discovery and Synthesis

et al. 2010

Self Cite

View full text Add to dashboard Cite

Sizable resources, both financial and human, are invested each year in the development of new pharmaceutical agents. However, despite improved techniques, the new compounds often encounter difficulties in satisfying and overcoming the numerous physicochemical and many pharmacological constraints and hurdles. Oxetanes have been shown to improve key properties when grafted onto molecular scaffolds. Of particular interest are oxetanes that are substituted only in the 3-position, since such units remain achiral and their introduction into a molecular scaffold does not create a new stereocenter. This Minireview gives an overview of the recent advances made in the preparation and use of 3-substituted oxetanes. It also includes a discussion of the site-dependent modifications of various physicochemical and biochemical properties that result from the incorporation of the oxetane unit in molecular architectures.

show abstract

“…We chose compound 20 as our key target based on a combination of its potential to be a piperazine mimic, [16] its achiralilty, and relative scarcity in published examples.…”

Section: Analysis Of Ideas For Noveltymentioning

confidence: 99%

A Practical Method for Targeted Library Design Balancing Lead‐like Properties with Diversity

et al. 2009

View full text Add to dashboard Cite

A practical and pragmatic method is demonstrated that aligns lead-like properties with compound diversity for the picking of compounds to synthesise from large virtual libraries. Methods are highlighted for decreasing synthetic attrition through the prior filtration of reagents sets grouped by reaction type. Also disclosed are protocols that use a combination of predicted physicochemical parameters and potential toxicological liabilities to enable the synthesis of lead-like compounds with a low potential risk of exhibiting toxicity or undesirable physicochemical properties. Lastly, a compound-picking process for a 2D compound matrix is demonstrated that maximises the diversity coverage whilst minimising synthetic effort. Thus a very highly optimised process is shown that delivers premium sample quality where lead-likeness and novelty are aligned to afford the best possible enhancement for the corporate compound collection.

show abstract

2,6-Diazaspiro[3.3]heptanes: Synthesis and Application in Pd-Catalyzed Aryl Amination Reactions

Abstract: A concise and scalable synthesis of a 2,6-diazaspiro[3.3]heptane building block is reported. The usefulness of this structural surrogate of piperazine is shown in arene amination reactions yielding a variety of N-Boc- N'-aryl-2,6-diazaspiro[3.3]heptanes.

Cited by 66 publications

References 11 publications

Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

Oxetanes as Versatile Elements in Drug Discovery and Synthesis

A Practical Method for Targeted Library Design Balancing Lead‐like Properties with Diversity

Contact Info

Product

Resources

About